EP0307002B1 - Verfahren zur Herstellung eines Antithrombin III-Konzentrates - Google Patents
Verfahren zur Herstellung eines Antithrombin III-Konzentrates Download PDFInfo
- Publication number
- EP0307002B1 EP0307002B1 EP88115353A EP88115353A EP0307002B1 EP 0307002 B1 EP0307002 B1 EP 0307002B1 EP 88115353 A EP88115353 A EP 88115353A EP 88115353 A EP88115353 A EP 88115353A EP 0307002 B1 EP0307002 B1 EP 0307002B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- antithrombin iii
- heparin
- complex
- heparinoid
- protamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 102000004411 Antithrombin III Human genes 0.000 title claims abstract description 36
- 108090000935 Antithrombin III Proteins 0.000 title claims abstract description 36
- 229960005348 antithrombin iii Drugs 0.000 title claims abstract description 36
- 239000012141 concentrate Substances 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title description 4
- 229960002897 heparin Drugs 0.000 claims abstract description 41
- 229920000669 heparin Polymers 0.000 claims abstract description 41
- 239000004019 antithrombin Substances 0.000 claims abstract description 31
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229920001499 Heparinoid Polymers 0.000 claims abstract description 16
- 239000002554 heparinoid Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 5
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 5
- 150000001450 anions Chemical class 0.000 claims abstract description 3
- 239000012266 salt solution Substances 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 21
- 102000007327 Protamines Human genes 0.000 claims description 18
- 108010007568 Protamines Proteins 0.000 claims description 18
- 229940048914 protamine Drugs 0.000 claims description 16
- 239000006228 supernatant Substances 0.000 claims description 6
- 239000002156 adsorbate Substances 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 239000000499 gel Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000007975 buffered saline Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 4
- 235000011130 ammonium sulphate Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229950008679 protamine sulfate Drugs 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000012443 analytical study Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 239000003618 borate buffered saline Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001155 isoelectric focusing Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
- C07K14/8128—Antithrombin III
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
- Y10S530/83—Plasma; serum
Definitions
- the invention relates to a process for the preparation of an antithrombin III concentrate, wherein first human plasma or antithrombin III-containing plasma fractions are mixed with heparin or heparinoid complex to form an antithrombin III-heparin or antithrombin III-heparinoid complex, and subsequent cleavage of the antithrombin III-heparin or.
- Antithrombin III-heparinoid complex with protamine is provided.
- Antithrombin III is known to have pharmaceutically valuable properties; in particular, the presence of antithrombin III in the production and storage of concentrates of highly effective coagulation factors and other plasma proteins with biological activity suppresses enzymatically caused protein changes which can result in undesirable side reactions on the patient.
- Other pharmaceutically valuable properties of antithrombin III are the effectiveness against thromboembolism in congenital deficiency of antithrombin III as well as in high-risk patients in whom antithrombin III drop occurs under heparin therapy.
- M. Miller-Andersson et al. in throm. Res. 5 , 439 (1974) describes a method for obtaining antithrombin III by affinity chromatography, antithrombin III being adsorbed on heparin agarose and further purification using ion exchange chromatography and gel filtration.
- the object of the invention is to be able to produce antithrombin III concentrates with high purity and yield using a process of the type mentioned at the outset, and is characterized in that in the first stage the antithrombin III heparin or antithrombin III heparinoid formed Complex adsorbed on an anion exchanger, the adsorbate eluted through a salt solution, the antithrombin III-heparin or antithrombin III-heparinoid complex contained in the eluate from salts and undesired
- Proteins is separated and in the second step, the solution of the antithrombin III-heparin or antithrombin III-heparinoid complex enriched in the purified complex is treated with immobilized protamine, the complex being cleaved and heparin being bound to the immobilized protamine, whereupon the Antithrombin III-containing supernatant is brought into durable form by lyophilization.
- the antithrombin III-heparin complex was precipitated from the combined eluates by adding 1.4 kg of ammonium sulfate and adjusting the pH to 5.5.
- the ammonium sulfate concentration of 430 g / l used here corresponds to an 80% saturation of the solution.
- the precipitate was separated by filtration and together with 13.5 g NaCl and 221 g Na3 citrate. 2 H2O dissolved in 1.5 l of distilled water.
- the pH was adjusted to 7.5 and to inactivate any viruses that were present, the mixture was heated at 60 ° C. for 10 hours.
- the pasteurized product was dialyzed against 50 l of isotonic saline and, for further purification, 1 l was stirred in at a pH of 7.0 303 g of ammonium sulfate.
- the ammonium sulfate concentration of 270 g / l used here corresponds to a 50% saturation of the solution. After 45 min stirring at + 4 ° C, the precipitate was separated by centrifugation and discarded.
- the supernatant was dialyzed against 100 l of a citrate-buffered, isotonic saline solution and concentrated by ultrafiltration to an antithrombin III content of 50 U / ml.
- Enzymatic Activity of Antithrombin III The activity was based on a standard preparation which had been soaked against Antithrombin III Plasma Human (1st Int. RP 72/1). With this standard preparation, a calibration curve was determined on which the samples to be tested were read.
- the activity was based on a standard preparation that was used against the 3rd Int. Stand. Heparin 65/69 had been calibrated. With this standard preparation, a calibration curve was determined on which the samples to be tested were read.
- the samples and the standard were diluted to activities of 0.001 to 0.5 IU / ml using a buffer solution of the following composition:
- protamine gel An immobilized protamine, a so-called protamine gel, is required for this procedure.
- Such gels can be made in various ways. Two methods are listed below.
- 1 l of a cross-linked 6% agarose gel (Sepharose Cl-6B) is suspended in 2 l of a 1 M Na2CO3 solution and with a solution of 100 g BrCN in 100 ml acetonitrile at a pH of 11.0 to 11.5 and a temperature of 5 to 10 ° C activated.
- the protamine gel Before use to remove heparin, the protamine gel is equilibrated with a tris and citrate buffered saline solution with a pH of 8.0.
- oxirane acrylic resin (Eupergit C) are mixed with a solution of 400 mg of protamine sulfate in 20 ml of 1 M potassium phosphate with a pH of 9.5 and left to stand for 16 hours at room temperature. After washing with water, 1 M NaCl solution and 0.01 M phosphate solution, the remaining reactive groups are blocked with 70 ml of a 5% solution of beta-mercaptoethanol (16 h at room temperature). Finally, it is washed five times with 80 ml of water each. Before use to remove heparin, equilibrate as in Method 1.
- the antithrombin III-heparin complex prepared as described above was dissolved or the solution obtained after the dialysis was used. 1 g of Tris was added to each 1 l of this dialyzed solution, the pH was adjusted to 8.0 and 15 ml of the protamine gel prepared by method 1 were added. After stirring overnight, the gel was separated by filtration; most of the heparin-free antithrombin III was in the adsorption supernatant.
- the gel was washed with tris and citrate-buffered saline solutions of increasing ionic strength.
- the adsorption supernatant and the heparin-free wash supernatants were combined to isolate antithrombin III and lyophilized to concentrate.
- the powder thus obtained was suspended in 1 ml of distilled water, 1 g each, and dialyzed against a citrate-buffered, isotonic saline solution. After dialysis, the mixture was diluted to an antithrombin III content of 50 U / ml, it was sterile filtered, bottled and freeze-dried.
- the enzymatic analysis showed a heparin content of less than 0.5 U heparin per 1 U antithrombin III.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Materials For Medical Uses (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0185983A AT379310B (de) | 1983-05-20 | 1983-05-20 | Verfahren zur herstellung eines antithrombin iii-heparin- bzw. antithrombin iii-heparinoidkonzentrates |
| AT1859/83 | 1983-05-20 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP84890084.1 Division | 1984-05-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0307002A1 EP0307002A1 (de) | 1989-03-15 |
| EP0307002B1 true EP0307002B1 (de) | 1991-11-21 |
Family
ID=3522546
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP88115353A Expired - Lifetime EP0307002B1 (de) | 1983-05-20 | 1984-05-10 | Verfahren zur Herstellung eines Antithrombin III-Konzentrates |
| EP84890084A Expired EP0129534B1 (de) | 1983-05-20 | 1984-05-10 | Verfahren zur Herstellung eines Antithrombin III-Heparin- bzw. Antithrombin III-Heparinoid-Konzentrates |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP84890084A Expired EP0129534B1 (de) | 1983-05-20 | 1984-05-10 | Verfahren zur Herstellung eines Antithrombin III-Heparin- bzw. Antithrombin III-Heparinoid-Konzentrates |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4510084A (da) |
| EP (2) | EP0307002B1 (da) |
| JP (2) | JPS59222421A (da) |
| AT (3) | AT379310B (da) |
| CA (1) | CA1211371A (da) |
| DE (2) | DE3479503D1 (da) |
| DK (2) | DK167271B1 (da) |
| ES (1) | ES532641A0 (da) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58180162A (ja) * | 1982-04-19 | 1983-10-21 | 株式会社高研 | 抗血栓性医用材料 |
| US4820693A (en) * | 1986-05-22 | 1989-04-11 | Angiogenics, Ltd. | Method and composition for arresting angiogenesis and capillary, cell or membrane leakage |
| US4966890A (en) * | 1986-04-04 | 1990-10-30 | Angiogenics, Ltd. | Method and composition for arresting angiogenesis and capillary, cell or membrane leakage |
| AT391808B (de) * | 1986-11-03 | 1990-12-10 | Immuno Ag | Verfahren zur herstellung einer faktor viii (ahf)-haeltigen fraktion |
| JP2678249B2 (ja) * | 1988-06-22 | 1997-11-17 | 株式会社ミドリ十字 | アンチトロンビン−▲ｉｉｉ▼製剤 |
| CA1341379C (en) | 1988-04-28 | 2002-07-23 | Welfide Corporation | Purified antithrombin-iii and methods of producing the same |
| KR100330540B1 (ko) * | 1993-04-05 | 2002-09-04 | 웰파이드 코포레이션 | 안티트롬빈-iii액상제제및그안정화방법 |
| JPH08199580A (ja) * | 1995-01-24 | 1996-08-06 | Tetra:Kk | 斜面昇降装置 |
| US7045585B2 (en) * | 1995-11-30 | 2006-05-16 | Hamilton Civic Hospital Research Development Inc. | Methods of coating a device using anti-thrombin heparin |
| US6562781B1 (en) | 1995-11-30 | 2003-05-13 | Hamilton Civic Hospitals Research Development Inc. | Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates |
| US6491965B1 (en) | 1995-11-30 | 2002-12-10 | Hamilton Civic Hospitals Research Development, Inc. | Medical device comprising glycosaminoglycan-antithrombin III/heparin cofactor II conjugates |
| AT405739B (de) * | 1997-09-19 | 1999-11-25 | Immuno Ag | Verfahren zur reinigung von antithrombin iii |
| US5985582A (en) * | 1997-12-09 | 1999-11-16 | Sigma-Aldrich Co. | Thrombin-based assay for antithrombin III |
| US20140206844A1 (en) | 2013-01-18 | 2014-07-24 | Prothera Biologics | Methods for isolating blood products from an inter-alpha inhibitor protein-depleted blood product material |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3099600A (en) * | 1961-01-26 | 1963-07-30 | Ormonoterapia Richter Spa | Chromatographic purification of heparin |
| SE392038B (sv) * | 1971-09-08 | 1977-03-14 | Kabi Ab | Forfarande for isolering av antitrombin ur blod eller blodprodukter |
| US3920625A (en) * | 1973-06-19 | 1975-11-18 | Kabi Ab | Isolation of coagulation factors from biological material using cross linked sulfated, sulfonated carbohydrates |
| US4119774A (en) * | 1976-03-05 | 1978-10-10 | Ab Kabi | Heparin purification method |
| US4087415A (en) * | 1976-06-09 | 1978-05-02 | William L. Wilson | Antithrombin III |
| US4175182A (en) * | 1978-07-03 | 1979-11-20 | Research Corporation | Separation of high-activity heparin by affinity chromatography on supported protamine |
| JPS6011922B2 (ja) * | 1978-09-22 | 1985-03-29 | 天野製薬株式会社 | 高活性ヘパリンの製造法 |
| AT359646B (de) * | 1979-04-19 | 1980-11-25 | Immuno Ag | Verfahren zur herstellung von nebenwirkungs- freien plasmafraktionen |
| FR2472390A1 (fr) * | 1979-05-04 | 1981-07-03 | Merieux Inst | Procede de preparation de concentres de complexe prothrombinique hautement purifies, et concentres obtenus |
| GB2061687B (en) * | 1979-11-02 | 1983-04-13 | Kidd A W | Grass cutting machines and improved blade therefor |
| DD148297A1 (de) * | 1979-12-21 | 1981-05-20 | Bezirks Inst Fuer Blutspende U | Verfahren zur herstellung von prothrombinkomplexkonzentraten mit verminderter thrombogenizitaet |
| DE3036481A1 (de) * | 1980-09-27 | 1982-05-19 | EC Erdölchemie GmbH, 5000 Köln | Verfahren zur gemeinsamen herstellung von c 4 -oligomeren und alkyl-tert.-butylethern |
| US4446126A (en) * | 1980-09-30 | 1984-05-01 | Cutter Laboratories, Inc. | Antithrombin-heparin complex and method for its production |
-
1983
- 1983-05-20 AT AT0185983A patent/AT379310B/de not_active IP Right Cessation
-
1984
- 1984-05-10 AT AT88115353T patent/ATE69552T1/de not_active IP Right Cessation
- 1984-05-10 AT AT84890084T patent/ATE45747T1/de not_active IP Right Cessation
- 1984-05-10 DE DE8484890084T patent/DE3479503D1/de not_active Expired
- 1984-05-10 DE DE8888115353T patent/DE3485288D1/de not_active Expired - Fee Related
- 1984-05-10 EP EP88115353A patent/EP0307002B1/de not_active Expired - Lifetime
- 1984-05-10 EP EP84890084A patent/EP0129534B1/de not_active Expired
- 1984-05-16 DK DK241684A patent/DK167271B1/da not_active IP Right Cessation
- 1984-05-16 CA CA000454412A patent/CA1211371A/en not_active Expired
- 1984-05-18 ES ES532641A patent/ES532641A0/es active Granted
- 1984-05-18 US US06/611,639 patent/US4510084A/en not_active Expired - Lifetime
- 1984-05-19 JP JP59101637A patent/JPS59222421A/ja active Granted
-
1990
- 1990-12-07 DK DK292090A patent/DK168062B1/da not_active IP Right Cessation
-
1992
- 1992-07-28 JP JP4201213A patent/JPH07116235B2/ja not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59222421A (ja) | 1984-12-14 |
| DE3479503D1 (en) | 1989-09-28 |
| AT379310B (de) | 1985-12-27 |
| DE3485288D1 (de) | 1992-01-02 |
| CA1211371A (en) | 1986-09-16 |
| DK167271B1 (da) | 1993-10-04 |
| DK241684D0 (da) | 1984-05-16 |
| ES8602414A1 (es) | 1985-12-01 |
| EP0307002A1 (de) | 1989-03-15 |
| ATE69552T1 (de) | 1991-12-15 |
| EP0129534A3 (en) | 1985-12-04 |
| JPH053480B2 (da) | 1993-01-14 |
| DK241684A (da) | 1984-11-21 |
| ATA185983A (de) | 1985-05-15 |
| JPH05320198A (ja) | 1993-12-03 |
| DK292090D0 (da) | 1990-12-07 |
| EP0129534B1 (de) | 1989-08-23 |
| DK292090A (da) | 1990-12-07 |
| ATE45747T1 (de) | 1989-09-15 |
| JPH07116235B2 (ja) | 1995-12-13 |
| EP0129534A2 (de) | 1984-12-27 |
| ES532641A0 (es) | 1985-12-01 |
| US4510084A (en) | 1985-04-09 |
| DK168062B1 (da) | 1994-01-31 |
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